The overall objective of this research program is to gain understanding of the genetic, cellular, biochemical and molecular nature of premature atherosclerosis in diabetes mellitus. There are five interrelated projects: (1) The role of hyperglycemia, diabetic nephropathy and the development of central obesity with intensive insulinization in determining the levels, distribution and composition of lipoproteins: It is proposed that part of the excess incidence of premature disease is related to the dyslipidemia that results from these variables in diabetes; (2) Therole of diabetes on the interaction between lilpoproteins and proteoglycans of the artery wall: It is hypothesized that alterations in lipoprotein and or proteoglycans as a results of diabetes will facilitate their interaction in such a manner that would result in the retention of lipoprotein in the artery wall in diabetes; (3) The effect of diabetes on HDL-mediated cholesterol efflux: This project will evaluate how modifications of lipoproteins affect two distinct pathways of cholesterol efflux from cells, passive desorption and apolipoprotein-mediated efflux, and will focus on how changes in HDL structure in diabetes affects HDL function; (4) The role of non-enzymatic glycation of endothelial cell matrix proteins on the signaling pathways activated by physiologic fluid flow: The major hypothesis is that nonenzymatic glycation of extracellular matrix proteins makes them "slippery" and unable to participate normally in the transduction of physico-chemical signals in response to fluid flow, which is the primary determinant of the production of endothelial-derived nitric oxide, a critical mediator of vascular homeostasis; (5) Molecular mechanisms of oxidation damage in diabetes: The hypothesis is that oxidant stress due to glucose autoxidation and/or protein glycation results in highly specific biologically active reaction products that can be used to detect glucose-mediated oxidative damage in vivo. This focus on the effects of diabetes on basic biological mechanisms of atherosclerosis should help establish which alteration are preventable or reversible, and will provide a rational basis for the prevention of this major complication of diabetes.